Binge drinking is a pattern of alcohol consumption that is associated with significant cost and risk of harm at the level of the individual and societ. While binge drinking is frequently a component of alcohol use disorders, people without a diagnosable problem also binge drink and it is consequently of a great deal of relevance to society and researchers. In order to provide preventative or therapeutic strategies to combat this high-risk behavior, we need to better understand the neural and genetic substrates that underlie binge drinking. Neuropeptide Y (NPY) is one system that has been implicated in alcohol consumption in both humans and animal models. Consequently, the overarching goal of this project is to determine the role of NPY in binge-like drinking in a genetic model of drinking to intoxication. High Drinking in the Dark (HDID-1) mice have been selectively bred for high blood alcohol concentrations following limited access drinking, and consequently represent a genetic model of risk for binge-like alcohol consumption. Aim 1 will use immunohistochemistry to measure NPY in brain areas relevant to alcohol consumption in alcohol-naive mice that are genetically at risk for binge drinking (HDID-1) and mice that do not have this genetic susceptibility (heterogeneous stock; HS) to determine whether these genotypes differ in NPY levels. Aim 2 will then knock down the Npy gene in the central nucleus of the amygdala, where the HDID-1 mice show greater Npy mRNA levels than the HS mice, to attempt in a site-specific manner to reduce binge-like drinking in these animals. Aim 3 will begin to pinpoint specific aspects of the NPY system that could be modulated to alter drinking in the HDID-1 mice. NPY and NPY Y1 receptor (Y1R) expression will be mapped in the CeA in ethanol-nave and post-drinking HS and HDID-1 mice. Additionally, site-specific infusion of Y1R antagonists into the CeA will be used to attempt to reduce drinking in the HDID-1 mice, which will serve to further dissect the site-specific role of NPY in binge drinking. This proposal will test the hypothesis tha high Npy gene and protein expression in mice at genetic risk for binge drinking are in part responsible for the high-drinking phenotype of the HDID-1 line, and that Y1Rs in the CeA are necessary for this effect. PUBLIC HEALTH RELEVANCE: Binge drinking is a risky behavior with significant cost at both the level of the individual and society. The long- term goal of this study is to determine the role of neuropeptide Y in genetic risk for binge drinking and begin to determine possible substrates within this system for therapeutic targeting.